Abstract
We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Blast Crisis / blood
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Blast Crisis / drug therapy
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Drug Administration Schedule
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Drug Eruptions / etiology
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Endothelial Growth Factors / blood
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Farnesyltranstransferase
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Fatigue / chemically induced
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Female
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Fibroblast Growth Factor 2 / blood
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Hepatocyte Growth Factor / blood
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Humans
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Intercellular Signaling Peptides and Proteins / blood
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Interferon-alpha / blood
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myeloid, Accelerated Phase / blood
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Leukemia, Myeloid, Accelerated Phase / drug therapy
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Leukemia, Myeloid, Chronic-Phase / blood
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Leukemia, Myeloid, Chronic-Phase / drug therapy
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Lymphokines / blood
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Male
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Middle Aged
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Multiple Myeloma / blood
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Multiple Myeloma / drug therapy*
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Nausea / chemically induced
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / blood
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Primary Myelofibrosis / blood
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Primary Myelofibrosis / drug therapy*
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Quinolones / administration & dosage
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Quinolones / adverse effects
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Quinolones / pharmacology
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Quinolones / therapeutic use*
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Salvage Therapy
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Treatment Outcome
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Tumor Necrosis Factor-alpha / analysis
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Antineoplastic Agents
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Endothelial Growth Factors
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Enzyme Inhibitors
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Intercellular Signaling Peptides and Proteins
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Interferon-alpha
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Lymphokines
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Neoplasm Proteins
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Quinolones
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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Hepatocyte Growth Factor
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Alkyl and Aryl Transferases
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Farnesyltranstransferase
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tipifarnib